Pro-survival Bcl-2 Proteins are Modifiers of MYC-VX-680 Synthetic Lethality

The transcription factor encoded by the myelocytomatosis oncogene (MYC) is deregulated by distinct means in different human cancers. Aberrations include chromosomal translocation, amplification, mutation, enhancer activation and post-translational mechanisms that lead to MYC protein accumulation [1]. It is perhaps the most commonly deregulated oncoprotein and is linked to most of the hallmarks of cancer [2]. Yet, despite decades of research, targeting MYC’s transforming function is still somewhat enigmatic. Without a kinase domain, it has proven difficult to target with small molecule inhibitors and since MYC is an intracellular protein, it is currently inaccessible to large molecules such as antibodies. A promising alternative approach, that has yet to be fully realized clinically, is to target MYC overexpressing cells with compounds that are synthetic lethal to MYC. Cancers that may benefit from successful synthetic lethal targeting of MYC include various leukemias and lymphomas where MYC deregulation plays a significant role in malignancy [3-5].